This is an SBIR Phase I re-submission to fund proof of concept studies for the development of induced pluripotent stem (iPS) cells from a population of HIV/NeuroAIDS patients who abuse alcohol and/or other substances (i.e. cocaine, opium, etc). It has been accepted that alcohol and drugs of abuse are significant cofactors in the progression of human immunodeficiency virus (HIV)-induced disease. HIV infection, alcohol and drugs of abuse significantly affect the immune system as well as the central nervous system (CNS). In patients with HIV, abnormalities intersect to lead to a constellation of symptoms known as NeuroAIDS. The term "NeuroAIDS" includes a myriad of novel neurologic disorders which are a primary consequence of damage to the central and peripheral nervous system by HIV. The medical conditions include sensory neuropathy, myelopathy, HIV dementia, and cognitive/motor disorder abnormalities. In minority groups HIV infection and NeuroAIDS progression occur at a disproportionate rate. The existence of biological differences within an ethnic group which might exacerbate the rate of conversion to NeuroAIDS is unknown. More definitive research has to be performed to understand the underlying mechanisms of alcohol and drug abuse on NeuroAIDS, specifically examining neuroimmunity, latent CNS reservoirs, neurons and glial cells. We are proposing to create iPS cell from fibroblast samples collected from minority HIV patients who abuse alcohol and/or drugs. Like human embryonic stem cells (hESCs), iPS cells can self-renew indefinitely and can be differentiated into most cells of the human body, including the CNS. Furthermore, iPS cells can either be modified by targeted gene disruption or created from patients as disease specific cell lines. We have successfully differentiated iPS cells and hESCs into neuronal lineages to study the neurodegenerative effect of various drugs and known toxins such as alcohol. We have successfully identified genes that are differentially regulated by alcohol during neurogenesis. We believe iPS cells to be a powerful tool in gaining insight into which biomarkers are essential for the progression to NeuroAIDS in populations infected with HIV while abusing substances. Obtaining primary cells from a patient's brain would only exacerbate their current neurological problem. The success of this proposal will create the first cell line that is designed to look at biomarkers of NeuroAIDS. Published reports for drugs entering human clinical trials estimate costs to vary from $500 million to $2 billion depending on the therapy. The success rate for all new drugs entering phase I trials and the successful completion of product licensing for human use is approximately 9%, meanwhile, the success rate for CNS drug candidates to become marketed therapeutic is projected at 3%. Several drugs have been tested in phase I and II clinical trials for HIV-associated dementia (HAD), which is commonly associated with HIV/NeuroAIDS and unfortunately none of the studies were able to improve health conditions. There is clearly a need to increase productivity and decrease the cost of drug development using strategies that also encourage innovation while ensuring drug safety and efficacy. HIV/NeuroAIDS patient-derived iPS cells represent a model to study CNS development;function and disease and are a useful tool to complement in vivo experimentation. We propose that the current inefficiencies, high attrition rates, protracted R&D cycles and elevated cost associated with drug development can be reduced by the advent of HIV/NeuroAIDS patient derived iPS cells which are relatively inexpensive and can be used as a model for high- throughput in vitro analysis in first phase drug discovery and preclinical product development in the biotechnology and pharmaceutical industry. The Specific Aims of this Phase I application are: Specific Aim #1: To create iPS cells from fibroblast cells taken from substance abusing minorities and non-minorities with HIV/NeuroAIDS. Specific Aim #2: Differentiate iPS cells into neuronal and glial cell lineages. Successful completion of this work will support a Phase II application, with the goals of including a larger cohort for iPS cell development, toxicology screening and the product leading to FDA 510(k) approval. PUBLIC HEALTH RELEVANCE: There is clearly a need to increase productivity and decrease the cost of drug development to treat HIV/NeuroAIDS using strategies that also encourage innovation while ensuring drug safety and efficacy. We propose that the current inefficiencies, high attrition rates, protracted R&D cycles and elevated cost associated with drug development can be reduced by the advent of HIV/NeuroAIDS patient derived iPS cells which are relatively inexpensive and can be used as a model for high-throughput in vitro analysis in first phase drug discovery and preclinical product development in the biotechnology and pharmaceutical industry.